Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 15, Issue 6, Pages 1543-1554Publisher
WILEY
DOI: 10.1111/ajt.13157
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Funding
- Samsung Biomedical Research Institute [C-B1-302-1]
- National Research Foundation of Korea (NRF) - Ministry of Education, Science, and Technology [2011-0023257, 2012R1A2A2A01013810]
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)
- Ministry of Health & Welfare, Republic of Korea [HI12C1853]
- National Research Foundation of Korea [2011-0023257, 2012R1A2A2A01013810] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The spheroid culture method is an effective strategy for ex vivo expansion of an autologous therapeutic cell population. We investigated if cotransplantation of bone marrow-derived spheroids (BM-spheroid) formed using 3D culture of BM-derived mononuclear cells (BM-MNCs) could improve the posttransplant outcome of islet grafts using a mouse syngeneic marginal mass renal subcapsular islet transplantation model. Using green fluorescent protein transgenic (GFP-Tg) mice, the role of the BM-spheroids and the contribution of vessels derived from donors and recipients in grafted areas were assessed by immunohistochemistry. Compared to fresh BM-MNCs and nonspheroid remnant cells (BM-nonspheroid), the BM-spheroids, mainly composed of CXCR4(+)CD14(+) myeloid cells, showed higher angiogenic capacity, such as in vitro self-formed vessel structures; increased expression of angiogenic and chemoattractive factors; and incorporation into new vessel formation in basement membrane matrix plugs. BM-spheroid cotransplantation with islets improved the posttransplant outcomes in terms of glucose tolerance, serum insulin level, and diabetes reversal rate when compared with cotransplantation of BM-nonspheroids. Immunohistochemistry revealed that cotransplantation of the BM-spheroids increased vessel density, area of grafted endocrine and non-endocrine tissue, and cell proliferation. In conclusion, cotransplantation of islets and BM-spheroids improved islet function through facilitation of revascularization and an increase in cell proliferation and islet cell mass.
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